OTUD6A-Mediated Deubiquitination of PRDX1 Protects Against Oral Ulcer by Restoring Mitochondrial Function

Oral ulcers (OU), as the most highly prevalent and recurrent oral mucosal lesion, have an unclear pathogenesis that hampers the development of effective treatments. While emerging evidence suggests that deubiquitinating enzymes (DUBs) may play a role in oral diseases, their functions in OU remain unclear. In this study, we screened the expression of DUBs in tongue tissues from mice with OU and identified OTU domain-containing protein 6A (OTUD6A) as the most substantially downregulated DUB during OU progression. The functional studies demonstrated that OTUD6A deficiency exacerbated OU pathology in mice and, correspondingly, suppressed proliferation and migration while promoting apoptosis of human oral keratinocytes (HOKs). Mechanistic investigations revealed that OTUD6A directly bound to peroxiredoxin-1 (PRDX1) and cleaved its K48-linked polyubiquitin chains at lysine 136 site (K136) via the catalytic residue C152, thereby stabilizing PRDX1 in HOKs. Loss of OTUD6A led to PRDX1 degradation, which enhanced mitochondrial oxidative stress and dysfunction, ultimately impairing HOKs function, while OTUD6A overexpression rescued HOKs malfunction. Importantly, local administration of recombinant OTUD6A protein significantly accelerated OU healing in mice. Collectively, these results identify a new OTUD6A-PRDX1 axis in OU pathology and present OTUD6A as a promising therapeutic target for OU.